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ERC-AG - ERC Advanced Grant

Objective

In mammals, the liver is the peripheral integrator of nutrient availability and energetic needs of the entire organism. We recently demonstrated that dietary amino acids (AA) activate liver Estrogen Receptors (ER) and that, in case of food scarcity, the lowered circulating AA decrease liver ER activity and reduce IGF-1 synthesis with the consequent blockage of the estrous cycle.Here, we hypothesize that in females liver ERa is also a sensor of the endogenous signalling induced by transitions among reproductive stages and a key organizer for the changes required to adapt energy metabolism to reproductive necessities. Thus, we propose that in mammals liver ERa is regulated by reproductive functions and that, in case of ovary malfunctioning, the altered estrogenic signalling causes metabolic impairment leading to local and perhaps systemic disruption of energy homeostasis.To demonstrate our theory, we will explore: i) the molecular pathways activating liver ERa and the related ERa transcriptome by genome-wide analytical tools; ii) the hepatic metabolism and the systemic consequences of liver ER pharmacological and genetic manipulations by means of metabolomic technologies; iii) the association between altered signalling on liver ER and the onset of metabolic disorders; iv) the molecular interactions between ER and PPAR activity and the effect of estrogens on liver autophagy.WAYS research is facilitated by a series of tools such as ER conditional KO, reporter mice, arrays of genes known as target of liver ERa, and others generated by our laboratory in collaboration with EU groups in previous EU programs.The vision of the liver as a functional unit with reproductive organs constitutes a paradigm shift in our understanding of woman physiology; thus, the full comprehension of liver ERa activity and regulation will be a critical step for the conception of new therapies for several diseases affecting women including the metabolic syndrome or the non-alcoholic steatosis.